Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques

Abstract

Interleukin-7 (IL-7), the principal cytokine implicated in thymopoiesis and peripheral T-cell homeostasis, is presently under evaluation in human diseases characterized by persistent lymphopenia. Unexpectedly, before the eventual IL-7-driven T-cell expansion, all treated patients showed a profound T-cell depletion 24 hours after injection. The current study uses the rhesus macaque model to investigate the mechanisms involved in this IL-7-induced T-cell depletion. We identify a new critical function of IL-7 that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine, and the skin. This homing process was initiated after the induction of chemokine receptor expression by circulating T cells and the production of corresponding chemokines in target organs. Finally, we demonstrate that the IL-7-induced cell cycling is initiated within these organs before T cells migrate back into the bloodstream, indicating that T-cell homing is required for in vivo IL-7 function. (Blood. 2009;114:816-825)

Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

“…These points still require clarification, but it is important to note that similar data have been obtained in a recent trial with IL-7 in macaques, in which generalized migration of T cells occurred in several tissues, but not in the LNs, early after treatment with the cytokine. 24 T EM cells seem to be the preferential target of IL-15 stimulation in vivo, as demonstrated by our experiments and by other research groups. [9][10][11] Signaling through the IL-15 receptor is critical for lymphocyte stimulation, and CD122 expression on the cell surface mirrors the expansion in the peripheral blood, with the following hierarchy: NK ϳ CD8 ϩ Ͼ CD4 ϩ and T EM Ͼ T CM Ͼ ϾT N .…”

“…At day 2 after IL-15 injection, macaques experienced transient lymphopenia ( Figure 7B), which preceded T-and NK-cell expansion at day 8. This seems to be a common effect of other cytokines of the ␥-chain family, since early lymphopenia has been also described after administration of IL-7 23,24 and IL-21. 25,26 Redistribution of lymphocytes early after therapy thus indicates that stimulation by IL-15 occurs in peripheral tissues rather than in the circulation.…”

“…This is not only true as in response to IL-15 but also as in response to IL-7. 23,24,35,36 This could be explained, at least in part, by the differential expression of CD122 by different CD4 ϩ and CD8 ϩ T-cell subsets, whose baseline values were indicative of the magnitude of expansion at the peak of the response. CD4 ϩ and CD8 ϩ T cells constitute a unique pool and continuously compete for the same homeostatic space.…”

Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

“…23,26 R-sIL-7gly, produced and provided by Cytheris SA, was injected 3 days after the previous IFN-␣ injection.…”

IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa

“…6,7 This phenomenon may reflect events that occur naturally when endogenous IL-7 increases to suprahomeostatic levels in response to lymphopenia. Although data obtained in macaques have suggested that lymph nodes, parts of the intestine, and the skin may be homing sites for T cells after IL-7 injection, 10 the anatomical sites where homeostatic processes take place and the molecular mechanisms underlying the IL-7-driven homing and proliferation of T cells in peripheral tissues remain largely undefined.…”